Human neural stem cells have the potential to substitute for fetal tissue in central nervous system (CNS) transplantation strategies and to act as vehicles for the delivery of gene products to particular regions of the brain and spinal cord. Epidermal Growth Factor Receptor (EGFR) plays a role in determining properties of differentiated neural cells and we hypothesize that the EGFR plays an important role in determining the phenotype of human neural stem cells. Therefore, these studies will explore the growth, differentiation, survival, and motility properties of human neural stem cells in which EGFR signaling pathways are modified by genetic means. We will utilize erbB family receptor mutants that have been shown to activate or inhibit EGFR signals in order to test our model that EGFR signaling modulates the human neural stem cell phenotype. By modulating EGFR signaling, we propose to alter survival, proliferative, and motility phenotypes of neural stem cells in vitro and in vivo. We will assess the growth, survival and migration properties of these cells in the normal brain and the injured brain, using an experimental head injury model, with the rationale that normal and EGFR-modulated human neural stem cell clones will display distinct phenotypes in particular brain microenvironments. Finally, we will assess cognitive and motor improvements in brain-injured animals after neurotransplantation with the rationale that normal and EGFR-modulated human neural stem cell transplants modify functional outcome after closed head injury. The proposed studies have therapeutic implications for a wide array of neurological diseases, including traumatic CNS injury; neurodegenerative diseases including Parkinson?s and Alzheimer?s disease; single enzyme disorders; and glioblastoma multiforme.